N-aminoalkyl-2 5-cyclohexadiene-1-carboxamides

ABSTRACT

THIS INVENTION RELATES TO NEW N-AMINOALKYL-2,5-CYCLOHEXADIENE-1-CARBOXAMIDES OF THE GENERAL FORMULA   1-(R1-N(-R2)-(CH2)N-NH-CO-),2-R6,3-R5,5-R3,6-R2-   2,5-CYCLOHEXADIENE   AND TO ACID ADDITION SALTS THEREOF. THEY ARE USEFUL AS ANTI-FIBRILLATORY AGENTS.

United States Patent Ofice 3,631,102 N-AMINOALKYL-2,5-CYCLOHEXADIENE- l-CARIIOXAMIDES Venkatachala Lakshmi Narayanan, North Brunswick,

Frederic Peter Hauck, Somerville, and Frank Lee Weisenborn, Somerset, N..I., assignors to E. R. Squibb & Sons, Inc., New York, N.Y. No Drawing. Filed Apr. 23, 1969, Ser. No. 818,839 Int. Cl. C07c 103/44 US. Cl. 260557 R 6 Claims ABSTRACT OF THE DISCLOSURE This invention relates to new N-aminoalkyl-2,5cyclohexadiene-l-carboxamides of the general formula I R R R5 and to acid addition salts thereof.

They are useful as anti-fibrillatory agents.

BRIEF SUMMARY OF THE INVENTION The invention relates to new compounds of the formula wherein R and R each is hydrogen, hydroXy-lower alkyl or phenyl-lower alkyl. They may be the same or different. In addition R and R may join together with the nitrogen to which they are attached to form a five to six membered nitrogen heterocyclic. R R R and R each is hydrogen, lower alkyl or lower alkoxy, preferably ortho or meta to the amide function, at least two of these Rs being hydrogen, n is 2 to 5.

The lower alkyl groups represented by the symbols are straight or branched chain hydrocarbon radicals of up to 7 carbon atoms, e.g., methyl, ethyl, propyl, iso propyl, butyl, isobutyl, t-butyl or the like. The lower alkoxy, hydroxy-lower alkyl and phenyl-lower alkyl groups contain similar alkyl groups attached to the other substituent. The heterocyclic groups formed by the grouping include piperidino, pyrrolidino, morpholino, piperazino, these rings with a lower alkyl substituent, and hydroxylower alkylpiperazino.

DETAILED DESCRIPTION OF THE INVENTION The new compounds of Formula I may be produced by several alternative methods.

According to one method, a benzamide of the formula R4 COHEKOH h-N R R5 R0 wherein R is hydrogen or amino and the other symbols have the same meaning defined above.

may be reduced using an alkali metal such as sodium in liquid ammonia preferably in the presence of an alcohol like ethyl alcohol.

Patented Dec. 28, 1971 Alternatively, a substituted benzoic acid of the formula (III) l a 2 C 0 OH I R5 Ra may be reduced under the same conditions described above to obtain a substituted 2,5-cyclohexadiene-l-carboxylic acid of the formula IV) at 1 2.

COOH

l R5 Rt The acid of Formula IV may then be converted to the acid chloride 1 3 2 COOH by treatment with oxalyl chloride, thionyl chloride or the like. The reaction of the compound of Formula V with a substituted diamine (VI) R1 gives the compound of Formula I.

Alternatively, a compound of Formula IV may be reacted directly with a diamine of Formula VI, in the presence of an equivalent amount of dicyclohexylcarbodiimide in an inert solvent like tetrahydrofuran, chloroform, dioxane, methylene chloride or the like to form the compound of Formula I. Purification of the products of Formula I may be effected by chromatography on silver nitrate impregnated silica plates, for example.

In all of the foregoing formulas the symbols have the same meaning described above.

The bases of Formula I form salts by reaction with equivalent amounts of the common inorganic and organic acids. Such salts include the hydrohalides, e.g., hydrobromide, hydrochloride, sulfate, nitrate, phosphate, acetate, citrate, oxalate, tartrate, malate, succinate, benzoate, ascorbate, alkanesulfonate, e.g., methanesulfonate, arylsulfonate, e.g. benzenesulfonate, toluenesulfonate, etc. It is frequently convenient to purify or isolate the product by forming an insoluble salt. The base may be obtained by neutralization and another salt then formed by treatment with the appropriate acid.

Starting materials of Formula IV which may be used to obtain the products of this invention include, for example, benzoic acid, 2-methylbenzoic acid, Z-methoxybenzoic acid, S-ethylbenzoic acid, S-methoxybenzoic acid, 2,5-dimethylbenzoic acid, 2,5-dimethoxybenzoic acid, and the like.

Amines of Formula VI which may be used include, for example, ethylenediamine, propylenediamine, 1,3-di aminopropane, 1,4-diaminobutane, N-methylethylenediamine, N,N-dirnethylethylenediamine, N,N-diethylethylenediamine, N-hydroxyethylethylenediamine, N-benzylethylenediamine, 2-morpholinoethylamine, 2-pyrrolidinopropylamine, 2 (4 hydroxyethylpiperazino)ethylamine and the like.

The new compounds of this invention are useful as antifibrillatory agents, e.g., in arresting cardiac arrhythmia in animals, such as mice or dogs. For this purpose a compound of Formula I or a physiologically acceptable acid addition salt thereof may be incorporated in a conventional dosage form such as tablet, capsule, elixir, in-

jectable or the like along with the necessary carrier material, excipient, lubricant, butter or the like for oral or parenteral administration in single or divided doses of about 1 to 50 mg./kg./day, preferably about 2 to 15 4 (3) N [2 diethylamino)ethyl] 2,5 cyclohexadiene-1-carboxamide.To a solution of 4.7 g. (0.04 mole) of Z-(diethylamino)-ethy1amine in 50 m1. of dry benzene, a solution of 5.6 g. of (0.04 mole) of 2,5-cyclomg./kg., two to four times daily (ED =11 mg./kg. in 5 hexadiene-l-carboxylic acid chloride in 50 ml. of dry mice). benzene is added dropwise with stirring. The mixture is The following examples are illustrative of the invenstirred overnight at room temperature and then heated tion. All temperatures are expressed on the centigrade on a water bath for 15 minutes. The solvent is removed in scale, vacuo, the residue is made basic with dilute potassium carbonate solution, and extracted with chloroform. The Example l.N-[2-diethylamino)ethyl] 2,5- chloroform layer is dried (MgSO and concentrated to cyclohexadienyl-l-carboxamide give of y y li cyclohexadiene-l-carboxamide. METHOD A The product is purified by chromatography over (1) 2,5-cyclohexadiene-l-carboxylic acid-Ten grams AgNO3 lmpregnated slhca Plates- (0.082 mole) of benzoic acid are added to 100 ml. of METHOD B anhydrous ethanol a 2 three-necked flask equipped A mixture of 3.05 g. 0.025 mole) of 2,5-cyclohexawith a mechanical stirrer and with loose cotton plugs 111 diene l carboxylic acid 29 1025 mole) f 2-(di h 1 the slde necks. After the benzoic acid has dissolved, 600 aminmethylamine and 5 15 0025 mole) of di l ml. of liquid ammonia are added to the stirred solution. hexylcarbodiimide in 200 1 f methylene chloride is Then atom) of Sodium are eldded in small stirred at room temperature for hours. The precipitate p when about One-third of e Sodlum has been is filtered off, the solution concentrated and dissolved in added, the White Sodium Salt of the held PteeiPitateS and 200 ml. of chloroform. The chloroform extract is washed there is strong foaming of the reaction mixture. After all 27 with dilute Sodium Carbonate Solution, followed by 3X the Sodium has been Consumed, as evidenced y the P' a 150 ml. washings with water. The organic layer is dried Pearanee of the blue Color, mole) of (MgSO and concentrated to give 2.9 g. of product. It monium chloride is added cautiously. The mixture is is rifi d as in Method stirred for an additional hour and then allowed to stand until the ammonia has evaporated. METHOD 0 The residue is dissolved in 300 m1. of water. The solu- 00 A solution of 8.8 g. (0.04 mole) of N-[Z-diethyltion is poured onto 200 g. of ice and acidified to a pH amino)ethyl]benzamide in 125 ml. of absolute alcohol is of about 4 by addition of ml. of 10% hydrochloric added dropwise to 1 liter of liquid ammonia cooled in a acid. The resulting mixture is extracted with four 100 ml. Dry Ice-acetone bath. To this rapidly stirring solution, portions of peroxide-free ether, and the combined extracts or 4.6 g. mole) of Sodium Cut i t a l Pi ces are are washed with 50 ml. of a saturated aqueous solution of added over a 5 minute period. When the reaction is comsodium chloride and dried over 2 g. of anhydrous magplete as seen by the disappearance of the blue color, 21 nesium sulfate. The ether solution is separated from the g. of solid ammonium chloride are added and the solution drying agent and concentrated at room temperature under allowed to evaporate overnight. To the residue 500 ml. reduced pressure. The residual oil is distilled in vacuo to 40 of water are added and the mixture is extracted with give 9.1 g. (90%) of 2,5-cyclohexadiene-l-carboxylic methylene chloride. The extract is washed with water, acid, B.P. -98/0.01 mm. dried (MgSO and concentrated to give 7.1 g. of product.

(2) 2,5-cyclohexadiene-l-carboxylic acid.-To a solu- It is purified as in Method A. tion of 12.2 g. (0.1 mole) of 2,5-cyclohexadiene-l-carboxylic acid in 75 ml. of dry benzene, 30 ml. of oxalyl Examples 2 to 15 chloride in 25 ml. of benzene are added dropwise with 0 Following the procedure of Example 1 (Method A), cooling. The reaction mixture is stirred at room temperathe additional compounds shown in the third column of ture for an hour. The solvent and excess oxalyl chloride the table below are obtained by utilizing benzoic acid or are removed, and the residual oil is distilled in vacuo to the substituted benzoic acid in the first column and the give 7.8 g. (51%) of a liquid, B.P. 8082/ 13-15 mm. diamine in the second column as the principal reactants.

TABLE I R1 -C0NH(CH2)..-N R3 R2 I2N(CI'I2)n N I I I R COOH R, Hi I I R5 a -N N Phenyl substltuent n \R 2,5-cyclohexadienyl n R Example:

C3111 Ca 1 2 3 N a -N CsH1 C3111 /C2H5 /C-zH5 3 R2=CH3 2 N\ Rz CHa 2 N\ CzHs C2115 4 RQ OCHa R5=OCH3 2 '-N ICI'I2C6IIB Rz OCH: R5=OCH3 2 -NHCHgCeI'I5 5 R3=CH3 R5=CH3 3 "'N R3=OH3 R5=CH3 3 'N TABLE-Continued I I R1 R1 -o ONH(CH2)..N R3 R2 HzN (CH2) r-N I I I R R R5 Re C O OH I 1 R1 R1 Ra Ra -N N Phenyl substituent n R 2,5-cyclohexadienyl n R Example:

6 Ra==OCH3 2 N N R3=OCHa 2 -N N 7 2 -N NCHQCHgOII 2 N NCHzCHzOH /CH2CH2OH CHzCHzOH 8 R =CH3 3 -N\ R3=CH3 3 -N\ CHzCHzOH CH2CH2OH 9 Rz=CHa R O CH3 4 NHOH3 R2=CH R =O CH 4 NHOH /CH3 CH3 11 R =C2H5 2 N R3=C3H5 2 N\ CH3 C 5 2 s 02115 12 R =0 CzHs 3 N\ R3=O C2115 3 -N\ 13 R =CH3 R =CH3 2 NHCH3 Rg=CH R =CH 2 NHCH 14 R =OCH Bu -OCH; 3 NH: R2=OCH Ra=OCH 3 -N 2 CzHa C2H5 15 R =C H5 R5=CZH6 2 N\ R;=C H5 R =C H 2 --N\ CzHs 0211!:

Example l6.N-[2-(diethylarnino)ethyl]-2,5-cyclohexa- 2. A compound as in claim 1 wherein R, R R R diene-l-carboxamide hydrochloride To a cooled solution of 2.2 g. (0.01 mole) of N-[2- (diethylamino) ethyl] 2,S-cyclohexadiene-l-carboxamide in 10 ml. of isopropyl alcohol, 10 ml. of l N, ethereal- HCl is added. The solvent is evaporated in vacuo, and the product is crystallized from alcohol-ether to give N-[Z- (diethylamino)ethyl] 2,5-cyclohexadiene-l-carboxamide, hydrochloride.

What is claimed is:

1. A compound of the formula R R5 Ra wherein R and R each is hydrogen, hydroxy-lower alkyl, phenyl-lower alkyl or together with the nitrogen to which they are attached form a nitrogen heterocyclic of the group consisting of piperidino, pyrrolidino, morpholino, piperazino and hydroxy-lower alkylpiperazino, R R R and R each is hydrogen or lower alkyl at least two of R R R and R being hydrogen, and n is 2 to 5, and acid addition salts thereof.

R and R each is hydrogen and n is 2.

3. A compound as in claim 1 wherein R R R and R each is hydrogen, R and R each is lower alkyl and n is 2.

4. A compound as in claim 1 wherein R R R and R each is hydrogen, R and R each is ethyl and n is 2.

5. A compound as in claim 1 wherein two of R R R and R are ethyl and the other two are hydrogen, R and R each is ethyl and n is 2.

6. A compound as in claim 1 wherein R, R R and R each is ethyl, R and R each is hydrogen and n is 2.

References Cited Kuehne et al.: J. Am. Chem. Soc., vol. 81, pp. 4278-87 (1959).

HENRY R. JILES, Primary Examiner H. I. MOATZ, Assistant Examiner US. Cl. X.R.

260247.2 A, 268 R, 294 A, 326.3, 514 R, 5442;424- 248, 250, 267, 274, 324

mg rm STATES EATENT @FFEQE Q'HMQAT @i @EQTW Patent No. 9 v Based, December 28, 1971 Inventofls) Venkatachala Lakshmi Naravanan .et a1;

It is certified that error appears in the shove-identified patent and that said Letters Patent are hereby corrected as shown below:

a i Column l, formula (I) should read as follows 7 1 CONH (CH N Column 1, formula (II) 5 should read as follows 1 Column 2, formula (V) should read as follows cocl Column 6, -Claim 2 should be a 5 6 cancelled and Claims 3 to should 'be renumbered-as Claims 2 to 5.

Signed and sealed this 10th dayof July 1973. I

Attest: g

' EDWARD M.FLETCHER,JR.

Attesting Officer Rene Teg'tmeyer I Acting Commissioner of Patents 

